title: Tumor suppressor menin represses paired box gene 2 expression via Wilms tumor suppressor protein-polycomb group complex.
abstract: Tumor suppressor menin, the product of the MEN1 gene, plays a key role in controlling histone 3 lysine 4 trimethylation (H3K4me3) and gene transcription, which can regulate proliferation, apoptosis, and differentiation. However, little is known as to whether menin controls gene expression and cell proliferation and survival via regulating Polycomb group (PcG) protein complex/H3K27me3. Here we show that menin specifically represses transcription factor Paired box gene 2 (Pax2) through PcG-mediated H3K27me3 and Wilms tumor suppressor protein (WT1), a zinc finger domain-containing DNA-binding protein. Menin does not directly bind to the Pax2 locus, instead, it up-regulates WT1 expression. WT1 recruits PcG complex to the Pax2 promoter and represses expression of Pax2 through PcG-dependent H3K27me3. Moreover, WT1 also interacts with DNA methyltransferase 1 (DNMT1), and recruits DNMT1 to the Pax2 promoter, resulting in hypermethylation of CpG in the Pax2 promoter. Together, these studies have uncovered a novel epigenetic mechanism whereby menin regulates H3K27me3 and promoter DNA methylation via WT1 and suggest that WT1 protein plays an important, yet previously unappreciated role in regulating the function of the menin/PcG axis, H3K27 methylation, and DNA methylation, resulting in repression of gene transcription.
authors.affiliation: Department of Basic Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian, China 361005.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
authors.forename: De-quan
authors.initials: DQ
authors.lastname: Zeng
authors.forename: Yuan
authors.initials: Y
authors.lastname: Wu
authors.forename: Rong
authors.initials: R
authors.lastname: Zheng
authors.forename: Le
authors.initials: L
authors.lastname: Gu
authors.forename: Xiao
authors.initials: X
authors.lastname: Lin
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Jin
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D018899:CpG Islands; D004247:DNA / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051762:PAX2 Transcription Factor / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014162:Transfection; D025721:WT1 Proteins / Q000378:metabolism
chemical_list: C484898:Men1 protein, mouse; D051762:PAX2 Transcription Factor; D011518:Proto-Oncogene Proteins; D025721:WT1 Proteins; D004247:DNA; D056484:Jumonji Domain-Containing Histone Demethylases; C523761:Kdm6b protein, mouse